Congestive Heart Failure, Tachycardia
Conditions
Keywords
Defibrillator, Cardiac Resynchronization Therapy, MADIT
Brief summary
The MADIT-CRT trial is designed to determine if combined implantable cardiac defibrillator (ICD)-cardiac resynchronization therapy (CRT-D) will reduce the risk of mortality and heart failure (HF) events by approximately 25%, in subjects who are in New York Heart Association (NYHA) functional Class II with non-ischemic or ischemic cardiomyopathy and subjects who are in NYHA functional Class I with ischemic cardiomyopathy, left ventricular dysfunction (ejection fraction \[EF\] \< or = 0.30), and prolonged intraventricular conduction (QRS duration \> or = 130 ms).
Detailed description
In this study, subjects will be randomized to CRT-D or ICD-only. Randomization will be stratified by clinical center and ischemic status. Approximately 60% of the subjects will be randomly assigned to receive a CRT-D with biventricular pacing, and 40% will receive an ICD only. Optimal pharmacological therapy for heart failure will be required in both treatment arms. Length of follow-up for each subject will depend on the date of entry into the study, since all subjects will be followed to a common study termination date.
Interventions
Boston Scientific Corporation Market Released Cardiac Resynchronization therapy with defibrillation
DEVICEImplantable Cardioverter Defibrillator (ICD)
Boston Scientific Corporation Market Released Implantable Cardioverter Defibrillator
Sponsors
University of Rochester
Boston Scientific Corporation
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
21 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Ischemic heart disease defined as: * NYHA Class I or II for the past 3 calendar months prior to, and at the time of, enrollment; * one or more clinically documented (Q wave or enzyme positive) prior myocardial infarctions, but not within 3 calendar months of enrollment; and/or * one or more prior coronary artery bypass graft surgeries or percutaneous coronary interventions (balloon and/or stent angioplasty) but not within 3 calendar months of enrollment. OR * Non-ischemic heart disease including dilated cardiomyopathy characterized by a low ejection fraction and increased ventricular volume, with ventricular compliance that is normal or increased * NYHA Class II for the past 3 calendar months prior to, and at the time of, enrollment AND all of the following: * Stable optimal pharmacologic therapy. * An ejection fraction \< or = 0.30 by angiographic, radionuclide, or echocardiographic methods within one year prior to enrollment and measured during the enrollment echocardiogram obtained within 14 days prior to randomization to confirm eligibility (recommended) * Resting QRS duration \> or = 130 ms on print-out of a current electrocardiogram (ECG) obtained within 14 days prior to randomization. * Sinus rhythm by ECG (including right bundle branch block \[RBBB\] and first degree heart block with PR \< 250 ms.) * Men and women 21 years of age or older (no upper-age cut off)
Exclusion criteria
* Existing indication for CRT * Subjects with an implanted pacemaker * Subjects with an existing ICD or CRT device * Subjects in NYHA Class I with non-ischemic cardiomyopathy * Subjects in NYHA Class III or IV in the past 3 calendar months prior to, or at the time of, enrollment * Coronary artery bypass graft surgery or percutaneous coronary intervention (balloon and/or stent angioplasty) within the past 3 calendar months prior to enrollment * Enzyme-positive myocardial infarction within the past 3 calendar months prior to enrollment * Subjects with angiographic evidence of coronary disease who are candidates for coronary revascularization and are likely to undergo coronary artery bypass graft surgery or percutaneous coronary intervention in the foreseeable future * Subjects with second or third degree heart block * Subjects with irreversible brain damage from preexisting cerebral disease * Women who are pregnant or plan to become pregnant during the course of the trial. Women of childbearing potential must have a negative pregnancy test within 7 days prior to enrollment. * Reversible non-ischemic cardiomyopathy such as acute viral myocarditis or discontinuation of alcohol in alcohol-induced heart disease * Subjects with chronic atrial fibrillation within one month prior to enrollment * Presence of any disease, other than the subject's cardiac disease, associated with a reduced likelihood of survival for the duration of the trial, e.g., cancer, uremia (blood urea nitrogen \[BUN\] \> 70 mg/dl or creatinine \> 3.0 mg/dl), liver failure, etc. * Subjects participating in any other clinical trials * Subjects unwilling or unable to cooperate with the protocol * Subjects who live at such a distance from the clinic that travel for follow-up visits would be unusually difficult * Subjects who do not anticipate being residents of the area for the scheduled duration of the trial * Subjects unwilling to sign the consent for participation
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Mortality From Any Cause or First Heart Failure (HF) Event | Outcome measured at average follow-up duration of 2.4 years. | MADIT-CRT was an event-driven trial in which patients were monitored for all-cause mortality and HF events. An HF event was defined as either hospitalization for symptoms and/or signs consistent with congestive HF and: 1. administration of intravenous decongestive therapy that does not involve formal in-patient hospital admission, regardless of the setting (i.e. in an emergency room setting, in the physician's office, etc.), or 2. administration of an augmented HF regimen with oral or intravenous medications during an in-hospital stay. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Recurrent Heart Failure Events | Time of event, DSMB review | The MADIT-CRT secondary outcome evaluated the effects of CRT-D, relative to ICD, on the recurrence of heart failure events over the full study period An HF event was defined as either hospitalization for symptoms and/or signs consistent with congestive HF and: 1. administration of intravenous decongestive therapy that does not involve formal in-patient hospital admission, regardless of the setting (i.e. in an emergency room setting, in the physician's office, etc.), or 2. administration of an augmented HF regimen with oral or intravenous medications during an in-hospital stay. |
Countries
United States
Participant flow
Recruitment details
The study enrolled 1820 patients from 110 hospital centers (88 in the United States, 2 in Canada, and 20 in Europe) between December 22, 2004 and April 23, 2008. Follow-up continued thereafter until trial termination.
Pre-assignment details
Data from all patients enrolled were analyzed on an intention-to-treat basis.
Participants by arm
| Arm | Count |
|---|---|
| Cardiac Resynchronization Therapy + Defibrillator Patients randomized to cardiac resynchronization therapy with backup defibrillation (CRT-D) in addition to optimal pharmacologic therapy (as administered by the primary care physician). CRT-D devices both deliver shocks to terminate potentially lethal ventricular arrhythmias and pace both ventricles in patients with ventricular dyssynchrony. | 1,089 |
| Implantable Cardioverter Defibrillator Alone Patients randomized to implantable cardioverter defibrillator (ICD) in addition to optimal pharmacologic therapy (as administered by the primary care physician). ICDs deliver shocks to terminate potentially lethal ventricular arrhythmias. | 731 |
| Total | 1,820 |
Baseline characteristics
| Characteristic | Cardiac Resynchronization Therapy + Defibrillator | Implantable Cardioverter Defibrillator Alone | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 546 Participants | 351 Participants | 897 Participants |
| Age, Categorical Between 18 and 65 years | 543 Participants | 380 Participants | 923 Participants |
| Age, Continuous | 65 years STANDARD_DEVIATION 11 | 64 years STANDARD_DEVIATION 11 | 65 years STANDARD_DEVIATION 11 |
| Region of Enrollment Canada | 14 participants | 8 participants | 22 participants |
| Region of Enrollment Czech Republic | 17 participants | 11 participants | 28 participants |
| Region of Enrollment Denmark | 22 participants | 13 participants | 35 participants |
| Region of Enrollment France | 13 participants | 9 participants | 22 participants |
| Region of Enrollment Germany | 98 participants | 61 participants | 159 participants |
| Region of Enrollment Hungary | 16 participants | 10 participants | 26 participants |
| Region of Enrollment Israel | 45 participants | 30 participants | 75 participants |
| Region of Enrollment Italy | 15 participants | 12 participants | 27 participants |
| Region of Enrollment Netherlands | 34 participants | 24 participants | 58 participants |
| Region of Enrollment Poland | 14 participants | 10 participants | 24 participants |
| Region of Enrollment Spain | 36 participants | 24 participants | 60 participants |
| Region of Enrollment Switzerland | 4 participants | 2 participants | 6 participants |
| Region of Enrollment United Kingdom | 4 participants | 3 participants | 7 participants |
| Region of Enrollment United States | 757 participants | 514 participants | 1271 participants |
| Sex: Female, Male Female | 275 Participants | 178 Participants | 453 Participants |
| Sex: Female, Male Male | 814 Participants | 553 Participants | 1367 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 126 / 1,079 | 0 / 712 |
| serious Total, serious adverse events | 164 / 1,079 | 55 / 712 |
Outcome results
Primary
Mortality From Any Cause or First Heart Failure (HF) Event
MADIT-CRT was an event-driven trial in which patients were monitored for all-cause mortality and HF events. An HF event was defined as either hospitalization for symptoms and/or signs consistent with congestive HF and: 1. administration of intravenous decongestive therapy that does not involve formal in-patient hospital admission, regardless of the setting (i.e. in an emergency room setting, in the physician's office, etc.), or 2. administration of an augmented HF regimen with oral or intravenous medications during an in-hospital stay.
Time frame: Outcome measured at average follow-up duration of 2.4 years.
Population: Analysis was performed on an intention-to-treat basis and counted the time to first event. The category Patients with Death at Any Time, includes deaths that occurred after the first heart failure event.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Cardiac Resynchronization Therapy + Defibrillator | Mortality From Any Cause or First Heart Failure (HF) Event | Patients who are Event Free | 901 Participants |
| Cardiac Resynchronization Therapy + Defibrillator | Mortality From Any Cause or First Heart Failure (HF) Event | Patients with Death or Heart Failure Event | 188 Participants |
| Cardiac Resynchronization Therapy + Defibrillator | Mortality From Any Cause or First Heart Failure (HF) Event | Patients with Heart Failure Event Alone | 152 Participants |
| Cardiac Resynchronization Therapy + Defibrillator | Mortality From Any Cause or First Heart Failure (HF) Event | Patients with Death at Any Time | 74 Participants |
| Implantable Cardioverter Defibrillator Alone | Mortality From Any Cause or First Heart Failure (HF) Event | Patients with Death at Any Time | 53 Participants |
| Implantable Cardioverter Defibrillator Alone | Mortality From Any Cause or First Heart Failure (HF) Event | Patients who are Event Free | 543 Participants |
| Implantable Cardioverter Defibrillator Alone | Mortality From Any Cause or First Heart Failure (HF) Event | Patients with Heart Failure Event Alone | 170 Participants |
| Implantable Cardioverter Defibrillator Alone | Mortality From Any Cause or First Heart Failure (HF) Event | Patients with Death or Heart Failure Event | 188 Participants |
Comparison: The trial utilized a Wang-Tsiatis (delta=0.1) group-sequential design with 95% power to detect a hazard ratio of 0.75 at a two-sided significance level of 0.05. Primary analysis based on statistical evaluation comparing the life-table event-free survival time graphs for CRT-D and ICD-only arms of the trial. Stratified Cox proportional-hazards regression was used to estimate a hazard ratio and statistical significance was evaluated with the log-rank test. Stratified by center and ischemic status.p-value: <0.00195% CI: [0.52, 0.84]Log Rank
Secondary
Recurrent Heart Failure Events
The MADIT-CRT secondary outcome evaluated the effects of CRT-D, relative to ICD, on the recurrence of heart failure events over the full study period An HF event was defined as either hospitalization for symptoms and/or signs consistent with congestive HF and: 1. administration of intravenous decongestive therapy that does not involve formal in-patient hospital admission, regardless of the setting (i.e. in an emergency room setting, in the physician's office, etc.), or 2. administration of an augmented HF regimen with oral or intravenous medications during an in-hospital stay.
Time frame: Time of event, DSMB review
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Cardiac Resynchronization Therapy + Defibrillator | Recurrent Heart Failure Events | Participants with 0 events | 928 Participants |
| Cardiac Resynchronization Therapy + Defibrillator | Recurrent Heart Failure Events | Participants with 1 event | 93 Participants |
| Cardiac Resynchronization Therapy + Defibrillator | Recurrent Heart Failure Events | Participants with 2 or more events | 68 Participants |
| Implantable Cardioverter Defibrillator Alone | Recurrent Heart Failure Events | Participants with 0 events | 545 Participants |
| Implantable Cardioverter Defibrillator Alone | Recurrent Heart Failure Events | Participants with 1 event | 107 Participants |
| Implantable Cardioverter Defibrillator Alone | Recurrent Heart Failure Events | Participants with 2 or more events | 79 Participants |
p-value: 0.00195% CI: [0.53, 0.86]Andersen-Gill